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Subtype-specific responses of hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids reveal an unconventional modulatory site and mechanism
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
KTH Royal Inst Technol, Sweden.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-3852-1015
KTH Royal Inst Technol, Sweden.
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2022 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e77672Article in journal (Refereed) Published
Abstract [en]

The K(V)7.4 and K(V)7.5 subtypes of voltage -gated potassium channels play a role in important physiological processes such as sound amplification in the cochlea and adjusting vascular smooth muscle tone. Therefore, the mechanisms that regulate K(V)7.4 and K(V)7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human K(V)7.4 and KV7.5 channels expressed in Xenopus oocytes. We report that PUFAs facilitate activation of hK(V)7.5 by shifting the V50 of the conductance versus voltage (G(V)) curve toward more negative voltages. This response depends on the head group charge, as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V-50 shifts. In contrast, PUFAs inhibit activation of hK(V)7.4 by shifting V-50 toward more positive voltages. No effect on V-50 of hK(V)7.4 is observed by an uncharged or a positively charged PUFA analogue. Thus, the hK(V)7.5 channels response to PUFAs is analogous to the one previously observed in hK(V)7.1-7.3 channels, whereas the hK(V)7.4 channel response is opposite, revealing subtype-specific responses to PUFAs. We identify a unique inner PUFA interaction site in the voltage-sensing domain of hKV7.4 underlying the PUFA response, revealing an unconventional mechanism of modulation of hK(V)7.4 by PUFAs.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd , 2022. Vol. 11, article id e77672
Keywords [en]
docosahexaenoic acid; electrophysiology; KCNQ; lipid; molecular dynamics simulations; omega 3; Xenopus
National Category
Biophysics
Identifiers
URN: urn:nbn:se:liu:diva-185818DOI: 10.7554/eLife.77672ISI: 000806620500001PubMedID: 35642964OAI: oai:DiVA.org:liu-185818DiVA, id: diva2:1669309
Note

Funding Agencies|Swedish Research Council [2017-02040, 2018-04905, 2021-01885]; Swedish Society for Medical Research

Available from: 2022-06-14 Created: 2022-06-14 Last updated: 2024-10-02
In thesis
1. Endogenous and Exogenous Molecules Modulating Voltage-Gated Potassium Channels
Open this publication in new window or tab >>Endogenous and Exogenous Molecules Modulating Voltage-Gated Potassium Channels
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The superfamily of voltage-gated potassium (KV) channels is crucial for the normal function of several tissues and represents an attractive pharmacological target for treating disorders such as epilepsy and cardiac arrhythmias. However, any drug designed to target a KV channel must be capable of discriminating between different members within the superfamily, lest they plague the user with deleterious side effects. Such rational design requires structural and functional insight into how the selectivity of a molecule can be tailored to suit the intended target.  

This thesis combines the use of electrophysiological and computational techniques to investigate the molecular basis for how the function of hKV7 and hERG channels can be modulated by different lipophilic compounds with known or suspected effects on ion channels. These include polyunsaturated fatty acids (PUFAs), cannabidiol (CBD), and synthetic cannabinoid receptor agonists (SCRAs).   

Using the two-electrode voltage clamp technique on Xenopus oocytes, we find that both PUFAs and CBD modulate the function of hKV7 channels in subtype-specific manners. PUFAs facilitated the activation of hKV7 channels, except for hKV7.4 channels which were instead inhibited. Molecular dynamics simulations revealed that structural differences in the voltage-sensing domain of hKV7.4 conferred a unique, inhibitory PUFA interaction site absent in the other hKV7 subtypes. Once this site was neutralised by mutagenesis, PUFAs facilitated hKV7.4 activation. In the case of CBD, we observed three different responses: inhibition of channels with hKV7.1 subunits, potentiated voltage-sensitivity of channels with hKV7.2 or hKV7.3 subunits and enhanced maximum conductance of channels with hKV7.4 or hKV7.5 subunits. However, these responses were evoked from the same interaction site in the pore domain, indicating a more complex subtype-specific mechanism of action. Finally, using an automated patch-clamp system we screened 36 different SCRAs on the cardiac channels responsible for repolarisation: hERG and hKV7.1/KCNE1. We find 28 of the SCRAs to be inhibitors of hERG and 22 to be inhibitors of hKV7.1/KCNE1. Molecular dynamics simulations suggest the increased susceptibility of hERG to SCRA-mediated inhibition may be due to a unique central cavity site that is absent from the pore domain of hKV7.1/KCNE1.   

In conclusion, structurally diverse lipophilic molecules of endogenous and exogenous origins can interact with KV channels and influence their function by enhancing or interfering with functional domains. In some instances, structural differences in the channel protein can explain the discrepancies in pharmacology. These findings have implications for both pharmacology (informing rational drug design) and toxicology (identifying targets through which adverse effects may occur).   

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2024. p. 129
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1931
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-208087 (URN)10.3384/9789180757522 (DOI)9789180757515 (ISBN)9789180757522 (ISBN)
Public defence
2024-11-08, Belladonna, Building 511, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Note

Updates:

2024-10-02 The thesis was first published online. The online published version reflects the printed version. 

2024-11-08 The thesis was updated with an errata list which is also downloadable from the DOI landing page. Before this date the PDF has been downloaded 94 times.

Available from: 2024-10-02 Created: 2024-10-02 Last updated: 2024-11-08Bibliographically approved

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